Deadly Mutation Knocks Out Organ Lining

Action Points

Integrin alpha-3 is a transmembrane integrin receptor subunit that mediates signals between the cells and their microenvironment and is involved in regulation of adhesion.

This report describes three patients with homozygous mutations in the integrin alpha-3 gene that were associated with disrupted basement-membrane structures. The patients had a multi-organ disorder that included congenital nephrotic syndrome, interstitial lung disease, and epidermolysis bullosa.

A fatal disorder of the kidneys, lungs, and skin in infants appears to be caused by mutations in a gene that regulates the thin layer of basement membrane tissue lining organs, researchers found.

Three such cases connected by common symptoms and homozygous mutations in the integrin alpha-3 gene were reported by Giuseppina Spartà, MD, of Children's Hospital Zurich, and colleagues in the April 19 issue of the New England Journal of Medicine.

All three patients had a congenital nephrotic syndrome with interstitial lung disease that ended up being fatal.

Fragile skin seen in each case was mild, but provided the clues that led to diagnosis, the researchers explained.

Mutations in integrin genes are associated with the connective tissue disorder epidermolysis bullosa with pyloric atresia as well as congenital muscular dystrophy, leukocyte adhesion deficiency, and Glanzmann's thrombasthenia.

Integrin is involved in adhesion of epithelial cells to basement membranes, which provides the structural and functional integrity of the organs. Integrin alpha-3 is a transmembrane integrin receptor subunit that mediates signals between the cells and their microenvironment, and is involved in regulation of adhesion.

The integrin alpha-3 genetic defect was first discovered in a baby boy who developed severe problems at birth, despite an uneventful pregnancy.

Immediately after delivery he had tachypnea and respiratory distress requiring high-flow oxygen support. A chest x-ray the same day showed severe changes in the lungs with a net-like pattern and nodular thickening.

At day 14, he still had respiratory distress with recurring life-threatening vomiting and aspiration episodes and was started on peritoneal dialysis due to renal failure and nephrotic syndrome. Ultrasound showed small, abnormally dense kidneys.

After three months, his skin started getting increasingly fragile with small, slowly healing blisters and erosions where it was rubbed. The child died from pulmonary infection at 7.5 months.

The researchers first looked at common mutations that cause congenital nephrotic syndrome and then at those that cause interstitial lung disease, but ruled out both.

Light microscopy and immunofluorescence of the boy's skin cells showed impaired epidermal adhesion and also basement-membrane assembly and remodeling problems.

"These abnormalities did not correspond to any known type of epidermolysis bullosa in humans but had striking similarities to the findings described in the integrin alpha-3 knockout mouse," Spartà's group explained.

With this clue, they went back and tested for integrin alpha-3 immunoreactivity in the skin, which turned up negative, suggesting loss of the protein. Basement membranes in kidney and lung samples also were "profoundly" abnormal.

Direct genetic sequencing for the gene confirmed the diagnosis and showed that both parents were unaffected, heterozygous carriers of the mutation.

Screening either other patients with congenital nephrotic syndrome turned up two similar cases homozygous for integrin alpha-3 mutations.

One girl developed respiratory distress and cyanosis two days after birth. At age 6 weeks, she was found to have diffuse interstitial lung disease and kidney problems requiring peritoneal dialysis.

She died from multi-organ failure at age 2 months.

A second girl developed fever and respiratory distress at age 2 months, at which time she was found to have pneumonia and proteinuria in the nephrotic range. Skin lesions and blisters consistent with epidermolysis bullosa started appearing at age 4 months.

Her kidney function deteriorated to require peritoneal dialysis at age 17 months, and she continued to have recurrent respiratory infections with the need for supplemental oxygen.

She died at age 19 months from multi-organ failure.

Unlike the other features, respiratory problems weren't expected from the mouse model of integrin alpha-3 mutations, the researchers noted.

The study was supported by a grant from the Federal Ministry for Education and Research, a grant from the Excellence Initiative of the German Federal Government and the Freiburg Institute for Advanced Studies School of Life Sciences–LifeNet, and grants from the National Institutes of Health.

Spartà reported having no conflicts of interest to disclose.

Reviewed by Zalman S. Agus, MD Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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